Alzheimer's disease (AD) is a progressive neurodegenerative disorder which in some (if not all) cases is inherited as an autosomal dominant trait. The first symptoms of AD can occur as early as the fourth to fifth decades of life. Alzheimer's disease is a major disease affecting over 3 million individuals in the U.S. alone at an annual cost of over $30 billion.
AD is characterized by progressive senile dementia with progressive loss of memory and motor functions. Prominent neuropathic features of AD include amyloid plaques, neurofibrillary tangles, and cerebral vascular amyloid deposits. Patterns of early-onset and late-onset AD have been reported in family inheritance studies. Analysis clearly indicates that AD is genetically heterogeneous. Numerous families have been described in which early-onset AD (onset &lt;60 years) appears to segregate as an autosomal dominant trait (1-8; see the appended Citations). Since onset of AD is rare in the fourth and fifth decades of life, familial clustering over multiple generations is unlikely to occur by chance. In one subset of early-onset familial AD (FAD) kindreds, mutations at codon 717 of the amyloid precursor protein (APP) gene are responsible for the disease (9, 10). Alison Goate, John Hardy, and co-workers (9) identified a single base change in codon 717 of the APP gene. Subsequently it was reported that this substitution in one mutation is responsible for an early-onset FAD in 2 kindreds. Shortly thereafter, Murrell et al. (11) and Chartier-Harlin et al. (10) identified two additional FAD mutations in the same APP codon. These mutations suggest that APP and deposition of the .beta.-peptide found in amyloid (.beta.A4) are central to certain AD disease processes. A total of 4 APP mutations causing .beta.A4 deposition have been identified: One at codon 693 which causes hereditary cerebral hemorrhage with amyloidosis of the Dutch-type (HCHWA-D; 10A), and three at codon 717 which cause FAD. These mutations are all found in exon 17 which, along with exon 16, encode the .beta.A4 peptide. The HCHWA-D mutation is a gln.fwdarw.gly mutation associated with .beta.A4 amyloid deposition (8). Despite the encouraging findings that APP mutations may be responsible for disease in certain families, it is now clear that these mutations are not associated with disease in the majority of FAD families with a high frequency of early-onset disease, including Volga German (VG) kindreds (17-21). In addition, FAD in most if not all late-onset kindreds does not appear to be associated with APP mutations (8,18,22). Thus, mutations in other as yet unidentified chromosomal locations may result in AD.
The role of inheritance in the more common late-onset AD is not presently resolved. Evidence that defective genes may be responsible for some or possibly all late-onset AD has been suggested by clustering of late-onset cases in individual pedigrees (8,14,22), family history data from case-control studies (23-26), and the concordance rates for mono- and di-zygotic twins (27-29). Certain data also suggest the possibility of "sporadic" AD, i.e., where no family history of disease is observed, that could result, for example, from noninherited genetic mechanisms such as somatic recombination or mutation.
The observation that APP mutations account for only a fraction of FAD confirms the hypothesis that the familial form of this disease is genetically heterogeneous (30,31). Evidence has been reported which suggests that an early-onset AD locus may exist on chromosome 21 that is centromeric to the APP gene (4,32). A late-onset AD locus has also been reported on chromosome 19 (14,33). However, many early-onset families do not map to chromosome 21 (8,18,22,34) or to chromosome 19 (14,37).
Two lines of evidence suggest that chromosome 19 may contain an FAD locus. First, a genetic association between FAD and an allele of a TaqI RFLP polymorphism was described by the present inventors at the Apo CII gene located at 19 q13.2 (12). The families analyzed were both early- and late-onset kindreds. Reevaluation of the Apo CII locus using a larger set of families (13) confirmed a statistically significant association between the locus and FAD, but the results of linkage analyses failed to show such an association in early-onset families and showed only a weak association (i.e., low positive LOD scores) with late-onset kindreds. The apparent conflict between the results of these two different analytic methods may indicate that a genetic model other than autosomal dominant inheritance may need to be applied to explain the genetic mechanisms operative in this type of AD.
The second line of evidence suggesting a chromosome 19 FAD locus comes from the work of Pericak-Vance et al. (14) who analyzed late-onset kindreds and reported statistically significant affected pedigree member results for BCL3 (a B cell chronic lymphocytic leukemia/lymphoma marker) and ATP1A3 (a subunit of the Na/K ATPase) at a significance level of p&lt;0.01. Both of the latter markers are located on chromosome 19 at q13.1-13.2 and are proximal to Apo CII. Two-point LOD scores for these loci and others in the region were suggestive of linkage of the disease with this region of chromosome 19, but the values did not reach a level of statistical significance. When early-onset (instead of late-onset) families were analyzed, the LOD scores were negative and the APM results were also not statistically significant. Multipoint genetic linkage analysis suggested a possible localization of an FAD gene locus in the vicinity of BCL3 and ATP1A3. A peak position score of over 4.0 was achieved when late-onset families were analyzed at the 1% penetrance level. In summary, although substantial evidence exists for a possible late-onset FAD locus in the vicinity of Apo CII and BCL3 on chromosome 19, this putative locus does not appear to be related to the genetic disease observed in early-onset AD families.
Relatively few markers have been described for chromosome 14, and the maps that have been described show genetic markers clustered within the proximal and distal portions of the q arm with an unconnected gap between the clusters. No polymorphisms have been mapped in the short arm of this acrocentric chromosome although a genetic map has recently been constructed using dinucleotide repeat polymorphic markers (56). Dinucleotide repeat polymorphism has also been reported in chromosome 14 marker D14S43 (55). No AD or FAD gene locus has previously been reported to be associated with chromosome 14.
At present there is no reliable method for presymptomatic or prenatal diagnosis of genetic predisposition for Alzheimer's disease. The search for additional genetic markers linked to AD has proven difficult because of the late age of onset and subsequent need for a large number of families and subjects for typing. Thus, while it may have appeared likely that at least one other AD locus remains to be identified, the existence of such a locus has not been reported.